Assoc Prof Toby Coates

Research Interests

ISLET TRANSPLANTATION AND DENDRITIC CELL BIOLOGY LABORATORY

Our laboratory is part of the School of Medicine and based in the newly amalgamated Central Northern Adelaide Renal and Transplantation Service on the 9^th Floor of the Royal Adelaide Hospital (East Wing). The group is run by Assoc Prof Toby Coates and our labs are situated in the Hanson Centre Laboratories on Frome Road.

Type I diabetes is a chronic, life-long autoimmune disease affecting over 140 000 Australians, where the insulin-producing islets of Langerhans in the pancreas are destroyed. The incidence of this disease is increasing and, even with daily insulin therapy, diabetic patients are at greater risk of serious complications including heart attack, stroke, ocular damage and kidney disease.

Our area of research focuses on the isolation and transplantation of healthy pancreatic islets as an innovative treatment and potential cure for Type I diabetes. As part of the Australian Islet Transplantation Consortium, the laboratory prepares and performs assays on purified islets that are ultimately transplanted into patients. To date, the Consortium has transplanted 15 patients across Australia. Factors limiting the success of islet transplantation include suboptimal engraftment, immune reaction and rapid cell death post transplant. Our laboratory is interested in identifying and combating the causes of islet cell death. We are also interested in basic islet biology, and how function can be protected/quickly restored following transplantation.

 

The laboratory is based in the Hanson Institute (Level 0, IMVS Main Building, Frome Rd). We are part of the Basil Hetzel Institute at the Queen Elizabeth Hospital site (http://tqeh.sa.gov.au/public/content/default.asp?xcid=1799) and the Robinson Institute Centre for Stem Cell Research (http://www.adelaide.edu.au/stemcell/). We reside within the Central Northern Adelaide Renal and Transplantation Service, where scientists regularly attend departmental meetings and many of the clinicians are heavily involved with research projects. We recently won a NHMRC project grant beginning in 2009 and we have active collaborations with groups bringing expertise in vascular biology (Dr Claudine Bonder, Centre for Cancer Biology http://www.centreforcancerbiology.org.au/Bonder.htm) and cellular neuroscience (Dr Damien Keating, Flinders University http://som.flinders.edu.au/FUSA/NEUROSCIENCE/molecular.htm).

CURRENT PROJECTS IN THE LABORATORY

Gene therapy to prevent apoptosis in transplanted pancreatic islets

Apoptosis is the major cause of islet cell death post-transplantation. Anti-apoptotic factors, such as insulin-like growth factor II (IGF-II), have the potential to protect transplanted islets. This project involves transferring DNA encoding protective genes, such as IGF-II, to islet cells using an adeno-associated virus gene therapy vector. Function and viability of transduced islets will be evaluated using techniques such as ELISA, cytokine challenge and flow cytometry. Transduced islets will be assayed for in vivo function in a diabetic NOD-SCID model.

 

Role of zinc transporters in pancreatic islets:

Another limitation of islet transplantation is the damage that occurs during isolation due to mechanical and enzymatic stress. This leads to apoptosis and an insufficient number of cells to meet metabolic needs post-transplantation. Zinc plays a vital role in DNA replication, enzyme activity and cellular protection against apoptosis and oxidative stress. Zinc is very high in pancreatic beta cells (the cells that secrete insulin) and is important in synthesis, storage and release of insulin. We have shown that levels of zinc transporter molecules on the surface of islet beta cells vary greatly among diabetic and non-diabetic patients. Our aim is to measure the RNA and protein levels of various zinc transporters in isolated and cultured islets and correlate this with protection of insulin production. The importance of zinc transporters in vivo will be assessed using a diabetic mice model.

 

Endothelial progenitor cells to promote the success of pancreatic islet transplantation in the rat

The islets of the pancreas are one of the most heavily vascularised tissues in the body, requiring 10% of the pancreatic blood flow despite only making up 1% of the pancreatic mass. As such, islets become rapidly hypoxic (inadequate oxygen supply) following isolation. Endothelial progenitor cells (EPC) are multipotent cells that act as a circulating ‘repair kit’ for vasculature, assisting with the repair of endothelium and the growth of new vessels in hypoxic or damaged tissue. EPC may improve the revascularization and engraftment of isolated islets following transplantation. The aim of this project is to characterize EPC by flow cytometry using antibodies against cell surface markers (including VEGF receptor 2, CXCR4, CD146, VCAM-1, monocyte markers (CD14) and stem cell markers (CD133, CD34)) and a 3D tube-forming assay in Matrigel. The cells will be evaluated for their potential to improve revascularisation when cotransplanted with pancreatic islets in a rodent model of diabetes.

 

Tolerogenic dendritic cells for transplantation

Dendritic cells (DC) are the sentinels of the immune system, potently directing the immune response towards a reactive or tolerant outcome. As such, DC are vitally important following the transplantation of organs and tissues. Our group has a long history in working with DC. Current projects involve characterizing the DC subsets present in the draining lymph nodes following kidney and islet transplantation. Another aim involves genetically modifying DC to induce a tolerogenic phenotype, and coadministering these DC to prevent transplant rejection.

 

Mesenchymal Stem Cells in Kidney Repair and Transplantation

In this project, we are exploring the therapeutic potential of ovine and human mesenchymal stem cells in kidney injury, with a particular emphasis on ischaemia reperfusion injury. Magnetic resonance imaging (MRI) is used to provide in vivo imaging of iron labelled MSC in a project supported by the Large Animal Research Imaging Facility (LARIF) in SA Pathology .

 

Publications

 

 

 

RECENT PUBLICATIONS

Non-human primate Dendritic cells. Jesudason S, Collins, MG, Rogers, NM, Kireta, S, Coates PT J Leuk Biol 2012:91:217-28

 

Early exposure of interferon-γ inhibits signal transducer and activator of transcription-6 signalling and nuclear factor κB activation in a short-term monocyte-derived dendritic cell culture promoting 'FAST' regulatory dendritic cells. Rojas-Canales D, Krishnan R, Jessup CF, Coates PT Clin Exp Immunol. 2012 Mar;167(3):447-58

Renal Dendritic Cells Adopt a Pro-Inflammatory Phenotype in Obstructive Uropathy to Activate T Cells, but Do Not Directly Contribute to Fibrosis. Snelgrove SL, Kausman JY, Lo C, Lo C, Ooi JD, Coates PT, Hickey MJ, Holdsworth SR, Kurts C, Engel DR, Kitching AR. Am J Pathol. 2012;180:91-103.

KHA-CARI adaption of the KDIGO clinical practice guideline for the care of kidney transplant recipients. Chadban S, Barraclough K, Campbell, S, Clark C, Coates PT, Cohney S, Cross N, Eris J, Henderson L, Howell M, Isbel N, Kannellis J, Kotwal S, Manley P, Masterson R, Mulley W, Murall K, O'Connell P, Pilmore H, Rogers N, Russ G, Walker R, Webster A, Wiggins K, Wong G, Wyburn K  Nephrology (Carlton).  2011 Dec 28.

Urinary tubular biomarkers as potential early predictors of renal allograft rejection” Ting YT, Coates PT, Walker RJ, McLellan AD. Nephrology (Carlton). 2011 Nov 3.

Ultrastructural analysis, zinc transporters, glucose transporters and hormones expression in new world primate (Callithrix jacchus) and human pancreatic islets. Mohanasundaram D, Drogemuller C, Brealey J, Jessup CF, Milner C, Murgia C, Lang CJ, Milton A, Zalewski PD, Russ GR, Coates PT. Gen Comp Endocrinol. 2011 Jul 29.

Amelioration of renal ischaemia-reperfusion injury by liposomal delivery of curcumin to renal tubular epithelial and antigen presenting cells Rogers NM, Stephenson M, Kitching A, Horowitz J, Coates PT. Br J Pharmacol. 2011 Jul 11

The Sphingolipid Rheostat: A Potential Target for Improving Pancreatic Islet Survival and Function. Jessup CF, Bonder CS, Pitson SM, Coates PT. Endocr Metab Immune Disord Drug Targets. 2011 Jun 22

Calcium supplements lower bone resorption after renal transplant Yu RW, Faull RJ, Coates PT, Coates PS "Clin Transplant 2011 August 21

Approaching the promise of operational tolerance in clinical transplantation. Bishop GA, Ierino FL, Sharland AF, Hall BM, Alexander SI, Sandrin MS, Coates PT, McCaughan GW. Transplantation. 2011 May 27;91(10):1065-1074

Curcumin induces maturation resistant dendritic cells that expand T reg cells in vitro and in vivo Rogers NM, Kireta S, Coates PT. Clin Exp Immunol. 2010 Dec;162(3):460-73.

Desensitization for renal transplantation: depletion of donor-specific anti-HLA antibodies, preservation of memory antibodies, and clinical risks. Rogers NM, Eng HS, Yu R, Kireta S, Tsiopelas E, Bennett GD, Brook NR, Gillis D, Russ GR, Coates PT. Transpl Int. 2011 Jan;24(1):21-9.

Gene Therapy to Improve Pancreatic Islet Transplantation for Type 1 Diabetes Mellitus. Hughes A, Jessup C, Drogemuller C, Mohanasundaram D, Milner C, Rojas D, Russ GR, Coates PT. Curr Diabetes Rev. 2010 Sep 1;6(5):274-84. Review

Calcific uremic arteriolopathy--the argument for hyperbaric oxygen and sodium thiosulfate.Rogers NM, Coates PT. Semin Dial. 2010 Jan;23(1):38-42.

Urinary soluble HLA-DR is a potential biomarker for acute renal transplant rejection. Ting YT, Coates PT, Marti HP, Dunn AC, Parker RM, Pickering JW, Jack RW, Kemp RA, Walker RJ, McLellan AD. Transplantation. 2010 May 15;89(9):1071-8.

Propagation and characterisation of dendritic cells from G-CSF mobilised peripheral blood monocytes and stem cells in common marmoset monkeys. Prasad S, Kireta S, Leedham E, Russ GR, Coates PT. J Immunol Methods. 2010 Jan 31;352(1-2):59-70. Epub 2009 Nov 18.

Review article: Kidney dendritic cells: their role in homeostasis, inflammation and transplantation. Rogers NM, Matthews TJ, Kausman JY, Kitching AR, Coates PT. Nephrology (Carlton). 2009 Oct;14(7):625-35. Review. Erratum in: Nephrology (Carlton). 2009 Dec;14(8):769. Kitching, Richard A [corrected to Kitching, A Richard].

Hyperparathyroidism and vitamin D deficiency predispose to bone loss in renal transplant recipients. Lim WH, Coates PS, Russ GR, Coates PT. Transplantation. 2009 Sep 15;88(5):678-83.

Clinical significance of anti-HLA antibodies detected by Luminex: enhancing the interpretation of CDC-BXM and important post-transplantation monitoring tools. Eng HS, Bennett G, Bardy P, Coghlan P, Russ GR, Coates PT. Hum Immunol. 2009 Aug;70(8):595-9. Epub 2009 Jun 12.

Monoclonal antibodies generated by DNA immunization recognize CD2 from a broad range of primates. Brady JL, Mannering SI, Kireta S, Coates PT, Proietto AI, Cowan PJ, D'Apice AJ, Lew AM. Immunol Cell Biol. 2009 Jul;87(5):413-8. Epub 2009 Feb 10

Human leucocyte antigen DQ alpha heterodimers and human leucocyte antigen DR alleles in tubulointerstitial nephritis and uveitis syndrome. Li JY, Yong TY, Bennett G, Barbara JA, Coates PT. Nephrology (Carlton). 2008 Dec;13(8):755-7.

Immunophenotyping of interstitial infiltrate does not distinguish between BK virus nephropathy and acute cellular rejection. Rogers NM, Russ GR, Cooper J, Coates PT. Nephrology (Carlton). 2009 Feb;14(1):118-22. Epub 2009 Jan 8.

Sphingosine kinase regulates the rate of endothelial progenitor cell differentiation. Bonder CS, Sun WY, Matthews T, Cassano C, Li X, Ramshaw HS, Pitson SM, Lopez AF, Coates PT, Proia RL, Vadas MA, Gamble JR. Blood. 2009 Feb 26;113(9):2108-17. Epub 2008 Dec 24.

Eng HS, Bennett G, Tsiopelas E, Lake M, Humphreys I, Chang SH, Coates PT, Russ GR. Am J Transplant. 2008 Nov;8(11):2335-42. Epub 2008 Sep 8.

Parental donors in live-donor kidney transplantation associated with increased rejection rates and reduced glomerular filtration rates. Lim WH, Chang SH, Coates PT, McDonald SP. Transplantation. 2007 Oct 27;84(8):972-80.

 

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Entry last updated: Wednesday, 29 Feb 2012